Met

The Met family of receptor tyrosine kinases (RTKs) contains two members in mammals, referred to as Met and Ron. Met is the receptor for hepatocyte growth factor/scatter factor (HGF/SF), while Ron is the receptor for macrophage stimulating protein (MSP).

In the adult, Met is predominantly expressed in epithelial and endothelial cells. Met regulates diverse cellular processes including cell scattering, proliferation and survival. It is involved in organ regeneration following kidney and liver damage. The Met and Ron receptors are essential for embryonic development as Met-/- and Ron-/- embryos die at E14.5-16.5 and E3.5, respectively. HGF/Met signaling is required for the development of the placenta, the liver and nervous system as well as the migration of myogenic precursor cells.

The Ron receptor is expressed in lineages of hematopoietic origin, in some epithelial cells, in cells of neuro-ectodermal origin and in osteoclasts. Ron is essential for embryonic implantation and is involved in a wide spectrum of physiological processes including the development of hematopoietic-derived cells, the inflammatory response of macrophages and bone resorption by osteoclasts.

Chronic activation of the Met or Ron receptors is associated with several human and murine tumors. Notably, the Met receptor was first identified in a cell line treated with a carcinogenic agent as a constitutively activated cytoplasmic oncoprotein, Tpr-Met, generated following chromosomal translocation. Met receptor amplification and/or overexpression have been reported in human tumors, including multiple carcinomas, some sarcomas and hematopoietic malignancies. Point mutations in the kinase domain of Met have been identified in hereditary and sporadic papillary renal carcinoma while mutations in the juxtamembrane domain have been identified in lung and gastric carcinomas. Ron is overexpressed in human breast and colorectal carcinoma. Three constitutively activated splicing variants of Ron have been identified in human gastric and colon cancer cell lines and in primary colorectal adenocarcinomas. Transgenic mice overexpressing Ron in lung epithelia developed multiple lung adenomas and adenocarcinomas.

Met and Ron are synthesized as a single polypeptide chain that is glycosylated. Upon translocation to the cell surface, Met is cleaved extracellularly by a furin protease to generate a disulphide-linked heterodimer composed of an extracellular α chain (307 amino acids) and a transmembrane β chain (1083 amino acids) that contains the intracellular kinase domain. The extracellular domain contains a Sema domain that is conserved in all semaphorins and plexins, a cysteine-rich PSI domain (found in plexins, semaphorins, and integrins), and four immunoglobulin-like repeats (also found in plexins). The Sema domain of Met, which is formed by the α chain and the first 212 residues of the β chain, is sufficient for HGF/SF binding.

Ligand binding to the Met and Ron receptors induces their homodimerization, activation of the kinase and trans-phosphorylation on tyrosine residues of the cytoplasmic domain. Phosphorylation of two conserved tyrosine residues located within the activation loop (Tyr1234/Tyr1235 in human Met, Tyr1238/Tyr1239 in human Ron) is required for activation of the intrinsic kinase activity of the receptor. A conserved twin tyrosine docking site (Tyr1349/Tyr1356 in human Met, Tyr1353/Tyr1360 in human Ron), located at the carboxy-terminus of the receptor, mediates substrate recruitment. The phosphorylated docking site directly recruits multiple signaling proteins containing either a Src-homology-2 (SH2) or a phosphotyrosine binding (PTB) domain. These include Grb2, Shc, SHP-1, the p85 subunit of PI3K, Stat3, and Src (Tyr1356 in human Met, Tyr360 in human Ron), as well as Gab1 (Grb2-associated binder-1), a scaffolding adaptor protein that is highly tyrosine phosphorylated upon Met and Ron activation. Gab1 is a major transducer of Met and Ron signaling. Gab1 is recruited directly to Tyr1349 in human Met and indirectly via Grb2. Gab1 recruits multiple signaling proteins including SHP-2, PLC-g, CrkII, CrkL and the p85 subunit of PI3K. These events induce the activation of downstream effectors such as the Ras-MAPK pathway, Akt, Src, Jnk, Rho, Rac1, Cdc42 and PAK, and are necessary for Met biological activity.

Activation of Met or Ron induces their ubiquitination, internalization and lysosomal degradation. Cbl ubiquitin-protein ligases are recruited directly to a juxtamembrane tyrosine in Met and Ron (Tyr 1003 in human Met, Tyr1017 in human Ron) and via Grb2. Downregulation of Met and Ron is essential for their normal biological activity and impairment of their downregulation leads to their oncogenic activation.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Family Members Met Ron/Sea
Other Names Hepatocyte growth factor (HGF)/Scatter factor (SF) receptor Stem cell-derived tyrosine kinase; STK
Molecular Weight
(kDa)
170 kDa (unglycosylated)
190 kDa (glycosylated - uncleaved)
α chain: 50 kDa; β chain: 145 kDa
170 kDa (unglycosylated)
185 kDa (glycosylated - uncleaved)
α chain: 35 kDa; β chain: 150 kDa
Structural Data 1390 aa 1400 aa
Isoforms Not Known Not Known
Species Vertebrates Vertebrates
Domain
Organization
Extracellular (Sema, cysteine-rich PSI, four immunoglobulin-like IPT)
Single-pass transmembrane
Cytoplasmic (tyrosine kinase)
Extracellular (Sema, cysteine-rich PSI, four immunoglobulin-like IPT)
Single-pass transmembrane
Cytoplasmic tyrosine kinase
Phosphorylation
Sites
Tyr1003
Tyr1234-Tyr1235
Tyr1349-Tyr1356-Tyr1365
Tyr1017
Tyr1238-Tyr1239
Tyr1353-Tyr1360
Tissue
Distribution
Epithelial tissues
Brain
Blood vessels
Peritoneal macrophages
Osteoclasts and megakaryocytes and skin gastrointestinal tracts
Brain
Subcellular
Localization
Plasma membrane
Endosomal-lysosomal pathway
Plasma membrane
Endosomal lysosomal pathway
Binding Partners/
Associated Proteins
Grb2
Shc
SHP-1
STAT3
Src
Gab1
p85 subunit of PI3K
RanBP9
β-Catenin
cbl
Grb2
PLCγ
Src
p85 subunit of PI3K
Shc
Upstream
Activators
Hepatocyte growth factor (HGF)/Scatter factor (SF)
Internalin B (InLB) of Listeria monocytogenes B1 ligand
Sema 4D
Macrophage-stimulating protein (MSP)
Plexin
Downstream
Activation
Akt
Src
Jnk
Rho
Rac1
Cdc42
PAK
Ras-MAPK
Disheveled (DVL)
GSK-3β
PI3K
PKCζbr> Src
JNK
MAPK
FAK
JNK
Activators Semaphorin 4D (SEMA4D) receptor
Plexin B1 (PLXB1)
CD44
Plexin B1 ligand
Sema 4D
Selective
Inhibitors
PHA-665752 (PZ0147)
SU11274 (S9820)
Not Known
Non-Selective
Inhibitors
K252a (K2015)
SU5416 (S8442)
Genistein (G6649, G6776)
Geldanamycin (G3381)
Not Known
Selective
Activators
Agonistic monoclonal antibody DO-24 Not Known
Physiological
Function
Cell proliferation
Morphogenesis
Motility
Regulator of macrophage function and inflammation
Disease
Relevance
Multiple carcinomas
Musculoskeletal sarcomas
Soft tissue sarcomas
Hematopoietic malignancies
Listeria infection
Malaria
Breast, gastric and colon carcinoma

 

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References